Regras de Permeabilidade de Drogas: 10 Anos Depois

T en years hav e passed since the pub lica tion of the \u2018rule of f ive \u2019 physical proper ty guideli nes for dr ug p erme a- bi l it y 1,2 . Th e r ul e of f ive , w h ic h w as d er iv ed f rom a da ta base o f cli nical can dida tes r eachin g Phase II trials o r further , states that poor absorptio n or permeab i lity are mo re like ly when c LogP (the calculat ed 1-octanol \u2013wa ter pa rti tion coeffi cien t) is >5 ; mol ec ul ar mas s is >50 0 dal to ns (Da); the number of hydr ogen-bond d ono rs (OH plus NH cou nt) is >5 ; and th e numb er of hydro gen- bon d ac cep to rs (O pl us N at om s) is >10 (RE FS 1,2 ) . Al tho ugh th e rule-of-f ive pr operties are interrela ted (cLo gP actual ly be ing a compo site proper ty dep end ent on mole cu lar siz e, pol arity and hydrogen bondi ng 3 ), its conc eptua l sim pli ci ty an d ease o f calcula tion has ma de i t the lea di ng mea sur e of dru g- lik ene ss , wi th the orig in al artic le ha ving mor e than 1,5 00 l it era ture cita tions. Th e ph ysi coch em ic al p r o file s of or al drug s 4\u20136 ar e co n- sist ent with the ru le of five, and recen t studies on drug ab sorp tion hav e a lso hig hlig h ted the impo rtanc e of pol ar surf ace ar ea (PSA) , which is closel y corr elated t o O plu s N at o m cou n t, an d LogD (1 -octa nol\u2013w a te r coeffic ien t at va rio us pH val ues) 7,8 . Ove rall o ral bi oa vai lab il ity depen ds no t ju st on ab sorp tio n but also o n dis solu tio n, gu t tran si t time an d fir st-pas s metabo lism, so it is pe rha ps su rpri s - ing tha t rat bioa vailabili ty can be categ orized b y sim ple ph ysical p roperti es s uch as PS A an d rota table bon ds 9,10 , and n umber of rule-of-five vio latio ns, PSA and ioniza - tio n sta te 11 . H ow ever , th es e mo de ls do not r ead il y exp la in h uma n bioa vaila bili ty data 12 . One furthe r aspe ct tha t has rec eiv ed less a tt en tion is tha t bulk mo lecular p ro perties a r e r el eva n t to dr ug saf et y as w e ll as ph arm ac o ki net ics an d met abo li sm: ma rk eted oral drug s, whic h are rule-o f-fi ve co mpl i ant 4\u20136 , hav e by d ef i nit io n su cc es sf u ll y p as se d rigoro us to xico logical and c linical sa fety hurdl es. Analyses of drug-likeness ine vitably depend on the medicinal chemistr y innovation and pr evailing strate - gi es of t he pa st. Howeve r , it is cle ar th at comp oun ds produced by more recent medici nal chemist r y e fforts do no t o c cu py t he s am e chemical space a s h is tor i ca l dr ug s. From th ree stu di es of ora l dr ugs 4\u20136 , th e m ean cLogP val ues wer e 2.3, 2.5 and 2.5 a nd mean m olecula r mass es were 3 33, 337 and 3 44 D a. B y contr ast, 1,1 17 Gla xoSm ith Kli ne compo unds 9 and 55 3 Abbo tt com - pound s 11 that had adv anced to pha rmacokineti c studies had, res p ectiv ely , mean cLogP values of 4.3 an d 3.9, a nd molecula r mass val ues of 48 0 an d 434 Da. A dditio nally , a gr oup of 1,6 80 op timized co mpound s fro m th e rece nt medici nal chem istry li terat ure h ad a m ean cLogP of 4. 0 an d mol ecula r mas s o f 43 5 Da 13 ; an d in an oth er l ite rat ur e stu dy , mo re th an 50% o f com pounds with high p ot ency ha d cL o gP va lu e s > 4. 25 an d mo le c ul ar ma ss v al ue s >425 Da 14 . Dru gs and research compounds a lso di ffer in physico chemic al proper ties b etwee n t arget protein clas s e s 13,15,16 and ther apy are as 17 . Mole cu lar mas s and other pro per ties o f oral drugs 6,17 , as we ll as of li terat ure com pounds 16 , a re also increas ing with tim e. Th es e c ha nge s a re p ot ent i al ly a c on ce rn b ec aus e ph ys i ca l p rop e r t y i n f l at i on ma y pr ove d e t ri m e nt a l to th e he alt h of d ru g d eve lopme nt pip el ine s. S e ver al studies 4,14,16,18 of comp oun ds in de vel opme nt c onc ur t ha t m e a n m o le c u l ar m as s d e cl i ne s a s c o mp ou n ds pr ogre ss throu gh Phase I, II and III; mor eo ver , the mo re Astr aZ eneca R&D Charn wood , Bake well Road, Loug hbor ough LE15 5RH, UK. Corr espondenc e to P .D.L. e-mail: pa ul .le eson @a st r az enec a.co m doi:1 0.1 038/nrd244 5 LogP Log of t he octan ol\u2013w ater part itio n coef fici ent, whic h is a mea sur e of a d rug\u2019 s lipo phil icity . Defi ned as the ra tio of u n-io niz ed drug dist ribu ted betwe en the oct anol and wat er p ha ses at equilib rium. Higher v alues imply greater lipophilicity . Mole cula r mass The molecu lar mass of a subs tan ce , fr eque ntly called mole cula r we ight , is the mass of one m olec ule of that subs tan ce , and its unit s are the unif ied atomi c mass unit (u) or Dalton (Da) , whi ch equals 1/12 t he mass of on e at om of carbon- 12. P olar surf ace are a (PS A). This is defined a s the surf ace s um ove r all p olar at oms , (u sual ly oxyg en and nitr ogen), also includin g att ache d hydr ogens . T he i nf l ue n c e o f d ru g - li k e c on c e pt s o n d e c i s i o n - m a k i n g i n m e d i c i n a l c h e m i s t r y P aul D. Leeson and Brian Springthorpe Abs tra ct | The app lic ation of guide lines linke d t o t he conce pt of dr ug- liken es s, suc h as the \u2018rule of five\u2019, has gained wide accep tanc e as an appr oach to r educe attrition in drug dis cover y and dev el opm ent. How eve r , despi te this acc ep tan ce , anal ys is of r ece nt tre nds r ev eal s that th e p hy sic al pr oper ti es of mol ec ule s that ar e curr entl y bein g s ynthe si zed in le adin g dru g di sco ve ry com pan ie s dif fe r si gni fi can tl y fr om tho se of re ce ntl y di sco ve r ed or al drugs and compoun ds in c linic al developm ent. The conseque nces of the marked incr ease in lipo phili city \u2014 the most important drug -like physi cal pro perty \u2014 include a g re ater likel ihood of lack of se lecti vity and attritio n in dr ug developm ent. T ackling the thr eat of compo und-r elated toxico logic al attritio n need s to mo ve to t he mainstr eam of medicina l chemi stry decisi on-ma king. NATU R E R EV IE WS | DRUG DISCO VER Y V O L U M E 6 | N O V E M B E R 2 0 0 7 | 881 A N A L Y S I S © 2007 N a ture Publi s hi n g G r o u p Bioa vaila bil ity This is the fraction of an oral dos e that rea ch es the sy ste mic circulation. Chem ical spac e This i s the s pace spann ed by all energ etic ally st able st oichi omet ric combin atio ns of elec tro ns , at omic nuc lei and to polog ies in mole cule s . Drug- lik e space may contai n 1 × 1 0 20 to 1 × 10 200 molecules. All these molecul es can ne ve r be made \u2014 to date 2 .7 × 1 0 7 mole cule s ha ve been repo rted . lipophilic compounds tend to be discontinued at each phase 4 . These obser vatio ns ar e likely to be the result o f developmen tal selection pr essures, combined with the increase in physical pro perties of com pounds enterin g drug develop ment. W it h a mea n ti me o f ~1 2 yea rs fr om dru g di sco very t o la un ch , an y a pp li ca ti on of dru g -li ke co nce pt s si n ce the la t e 19 90 s w ill ha ve onl y had a ma rgin al in flue nc e on t oda y\u2019 s la te -s ta ge d ev el o p men t pi pe lin es . Ho w ev er , th er e ha s be en am ple opport unity for drug-lik eness to hav e an impact Box 1 | Data collectio n and analysis Oral drugs. A n o ral d rugs database containing 2,118 drugs approve d worldwi de up to June 2007 was assembled from the Food and Dru g Adminis tra tion Orange book 56 and published databases 5,6, 57 . F or oral drugs launched since 1983 (592 drugs), the year of l aunch was co llecte d fro m l iter atur e compil ations 5 7,58 and the year o f first publicatio n of the drug (usually a patent 6 ) was obtained from Scifin der 59 and the Mer ck Inde x 60 . Promiscuity data. The Cerep BioPrint database (\u2018BioPrint\u2019 is a r egistered trademark of Cerep SA) 27,28 contains data on 2,133 compounds, mainly existing drugs and reference compounds, which have been tested in an in vitro panel of 200 r eceptor , enzyme and metabolic screens. Pr omiscuity is defined as the number of hits for each compound, for which >30% inhibition was found at a concentr ation of 10 µ M; compounds meeting this level of activity had IC 50 values determined. This is a larger data set than the BioPrint data examined pr eviously (1,098 compounds) 29 . Development compounds. Compounds originating with, or assoc iated with, the top 25 pharmaceuti cal companies 61 and in Phase I or I\u2013II ( n = 91), Phase II or II\u2013III ( n = 214), and Phase III or pr eregistr ation ( n = 126) wer e collected from the Pr ous Sci ence Integrity database (\u2018Integrity \u2019 is a reg ister ed tr ademar k of Pr ous) 57 in July 2007 . P atente d com pou nds . Da tab as es of th e mo st r ece nt ly pub lis he d co mpo un ds i n pa te nt app lic at ion s ori gin at ing fr om fou r ma jo r ph arm ac eut ic al c om pan ie s \u2014 As tr aZe nec a, G la xoS mi th Kli ne , Me rck a nd C o. , an d Pf ize r \u2014 wer e cur ate d fr om two so ur ce s, P r ou s Sci enc e In teg ri ty 57 an d GV K Bi o 62 . Pr ous Scienc e Int eg rit y dat a wer e co lle ct ed fr om Jan uar y 200 1 to Jun e 20 07 ; ov er thi s ti me per iod the fou r se le ct ed com pan ie s pr odu ced the lar ges t nu mbe r of pa tent a ppl ic at ion s co mp are d wi th o th er or gan iz atio ns. Pr ou s Sci ence In teg ri ty dat a in clu de com po und s fr om le ga cy o r gan iz at ion s no w me r ge d wi th th e se le cte d co mp ani es (Me r ck Fr oss t, and M er ck Sh ar p an d Do hme are a bst r ac ted sep ar ate ly and w er e add ed to th e Me r ck and C o. d at a). Com po un ds wit h mo lec ul ar mas s ,00 0 dal ton s we r e se lect ed fr om the e ar lie st p ha se, def in ed a s \u2018bi olog ic al tes ting\u2019 in Pr ous Science Int egr ity, wh ic h rem oves pa te nts on ex is ti ng dru gs an d deve lopm ent co mpou nds . The d at a we r e fu rthe r fil te r ed, by sel ect in g \u2018l ea d co mpo un ds\u2019 on ly \u2014 the Pro us Scien ce Int egr it y ab str act or s se lec te d (m os tly ) a sin gle com po und fro m th e pa ten t ap pl icat ion , ei th er a spe ci fic al ly cla ime d com pou nd , or t he e xa mpl e wi th the be st c it ed bio log ic al act ivi ty , or a comp oun d r ep res ent at ive of the o th ers in the p at ent . Fin all y, b as ic pat ent app li cat io ns , fi le d by t he P CT r out e (P at ent Co ope r at ion T r eat y for i nter nat io nal pat en t ap plic ati on s, \u2018WO \u2019 nu mbe r ed pat ents f ile d fr om 200 1 o nwar ds, >90 % of the tot al ) wer e s el ec te d, pr ovid ing th e y ea r of publ ic at io n. Thi s r esul ting da ta bas e c ontai ned 3,5 16 ent ri es f r om 3,3 89 WO pa te nts (8 55 Ast ra Ze nec a, 921 Gla xo Smi th Klin e, 82 2 Mer ck and 918 Pfi ze r en tr ies ). Unli ke Pro us Science Int egr ity , the avai lab le GVK Bio dat aba se is lim ited to compo und s patent ed in sel ecte d targ et clas ses onl y: kinas es, G PCR s (G-pr otein- coup led r ecep tor s), pr ote ase s, ion channe ls, tra nsp ort ers , nuclear hor mon e re cep tor s and phos pha tas es. GVK Bio abstr actors do not select spe cif ic compo unds ; instea d a co mpr ehens ive cove ra ge (som eti mes lim ited to 100\u20132 00 compo und s for a patent appl ication ) is p rovid ed. The data bas e was sea rc hed for WO pa te nt s fr om the four se le cte d c ompa nie s f or the peri od 20 03 \u20132 007 . Lega cy and asso ciat ed or gani zat ions ap pe ar ed to be inc lude d sepa r at el y in GVK Bio . Ther efo r e the sea r ch terms us ed in cl ude d t he na me s Mer ck & Co, Me r ck an d Co, Mer ck Fr osst , and Me r ck Sh arp fo r M er ck; Gla xo an d Smi thK line fo r Glax oSmi thK line ; Pfiz er , W arn er\u2013L am ber t, Up jo hn and Ph arma cia fo r Pfi ze r . As tr aZen ec a was use d a s a si ng le se ar ch term . Some pa te nt du pl ica tion s unde r t he diff er ent leg acy or gan izat io ns wer e fo un d and re moved . T he nu mb ers of co mp ou nds pe r p at en t fro m t he se se ar ches r an ge d fro m one to se ve r al hu nd r ed; to pro vi de a bala nc ed as se ssm ent of each pa te nt , the mea n and me di an phy si ca l pr ope rty data per pa tent we r e used in addi tio n t o the to ta l numb ers of comp ou nd s. T wo GVK Bio data base s res ulte d: GV K comp ounds con tain in g 117, 148 comp ound s (Ast r aZ en ec a = 25, 233, Gl ax oS mit hKli ne = 28,8 10 , Mer ck = 3 1, 32 7 and Pfi ze r = 31 ,7 78) , an d GV K pa te nts con ta inin g 1,9 03 WO pat ent s (A st raZ ene ca = 440 , Gl ax oSm it hK lin e = 497 , Me rc k = 519 a nd P fi ze r = 44 7) . In each database, GPCR t arg ets were assign ed accor ding to t he endoge nous ligand \u2014 that is, am ine, peptide or lipid 15 ,63 . Kinase, pro tease, io n channe l, tr ansport er and nuclear hormo ne rec eptor target cl asses were also as signed to the Prous Science Integr ity compounds, based on the abstract ed mechan ism of actio n. The GVK Bio a ssignm ents of these tar get classes were used as provided. The numbers of compounds and patents and 1983\u20132007 oral drugs in each ta rge t class examined is summ arized in S uppleme ntary informatio n S4 (table ). A ra ndom selection of chem ical structu res a nd paten t a ssignm ents from the asse mbled databases were checked for accuracy . Data analysis. Physical pr operty data wer e obtaine d fro m Astr aZenec a\u2019 s C-Lab too l, incor por ating standar d package s for LogP cal culati ons (cLogP , ACDLo gP), and an in-house algorithm for th e distri bution coefficien t (1-oct anol\u2013wa ter LogD at pH 7 .4). Other well-estab lished m olecula r pro perties 4\u20136,9,11 e xamined w ere p olar surface ar ea (PSA), t he hydr ogen-b ond donor an d accept or counts , the numbers of rings a nd rot ationa l bonds, the L ipinski s cor e (a value of 1 for each vio lation of t he rule of 5 per mo lecule , w ith maximum value of 4) , and the char ge stat e (acid, b ase, quaternary base, neutral o r zwitter ion). Statistica l analyse s wer e perfor med with JMP 64 and v isualiz ed with Spotfir e 65 . In line wit h rec ent practice 13 we ci te median r ather t han mean ph ysical proper ty values f or normal ly distr ibuted continuou s data (molecu lar mass an d c LogP), a lthough t he use of mean d ata does not m ateria lly change t he data or con clusion s rea ched. For full s tatisti cal details, including promiscui ty analys es and the r esults o f pair ed Student\u2019 s t-tests b etween compani es fr om JMP , s ee Supple mentar y informa tion S5 (box ). ANAL YSIS 882 | N O V E M B E R 2 0 0 7 | V O L U M E 6 w w w. n a t u r e . c o m / r e v i e w s /d r u g d i s c © 2007 N a ture Publi s hi n g G r o u p Natur e Review s | Drug Disco very Median cLogP Y ear 5 4 3 2 1 0 1965 1970 1975 1980 1985 1990 1995 2000 2005 \u20131 a Median molecular mass (Da ) Y ear 250 300 350 400 450 500 550 1965 1970 1975 1980 1985 1990 1995 2000 2005 b Launch Publication Launch Public ation Natur e Review s | Drug Disco very No. drugs launched or % molecular mass Launch year 60 70 80 50 40 30 20 10 1985 1990 1995 2000 2005 Per centage mo lecular mass Number launched on curr en t dec isi on -maki ng in med ici nal c hem ist ry . T o ex am in e th is, we de ci ded to co mp a r e th e ph ys ic oc hem ica l p r o fil es o f rec en tl y dis co ve r ed or al dru gs a nd co mp o un ds in dev el o p me n t wi th the mos t co nt emp o ra r y bi olo gic ally act iv e co mp ou nds : t ho se p ub lis he d in th e cur r en t pa te n t li tera tur e (fo r a de scrip tion o f da ta co llecti on a nd an al y- si s, see BO X 1 ). W e cho se to loo k a t pa ten t ap pli ca tio n s fo r sm all mo le cu le s or ig ina tin g fr om fo ur lar ge m ult in at io na l o r ga ni za tio n s: As tra Zen eca , Gl ax oS mi thK lin e, M er ck a n d Co., and Pf izer . These compa nies are the most pr olific co n trib uto rs of n ew pat en t app lica tio ns in thi s field a nd ha ve a sp rea d o f th era peut ic in ter est s cov erin g mos t ar eas o f cur r en t dru g di sco ve ry , as we ll a s a we alt h of kno w- h o w in dru g di sco ve r y a nd d eve lo pm en t. W e also exa min e the r el a ti o ns hi p be tw een ph y s ic al p ro pe rt ie s a n d d ru g p ro mi s- cui ty , o ne poss ible sour ce o f to xico log ical s ide e ffects. Or al dr ug s In oral dru gs approv ed since 1983, there are increas es with publication d ate 6 in three of t he four rul e-of-five properties (molecular mass, O plus N atom count and OH pl us NH c oun t), wher eas one (li pophilici ty , cLogP ) is chan ging less ap pr eciably (mo lecular mass and cLogP d at a a re s ho w n i n F I G. 1 ) . Me d i an m ol e c u l ar m as s inc rea sed sign ific an tly on a ver ag e b y 5.2 Da per publ ica - tio n year fro m 19 64\u2013 2001, and b y 2.2 Da per la unc h yea r fro m 1983\u20132 007. Gi ven the larg e increase in mo lecular mass and small cha ng e in c LogP , i t is not surprisin g that other rel ated bulk physic al proper ties \u2014 t hat is, PSA, rin gs and r ota tab le bon d co unt \u2014 ar e als o in cr easin g sig- nif ica ntl y with pub lica tio n tim e, whe re as oth er meas ure s of lip ophilicity (AZLo gD7.4) and p ercentage of PSA 17 ar e n ot ( Sup ple men tar y i nfo r ma tion S 1 ( tabl e)). F act or s dri vin g the incr eases in ph ysical pr ope rtie s in the most rece n tly disco ver ed or al drug s inc lu de a gre a te r nu mber of appa re ntl y l ess druggab le new targ ets 19, 20 , for whic h lar ger and mor e lipo phili c mole cules ap pear to be necessa ry fo r high affinity bi nding to active sit es \u2014 for ex ample, HI V prot eas e in hibit ors a nd a ntagon ist s of peptidic G-prot ein-coup led receptors (GPCRs) \u2014 and int en si ve o pt im iz at ion of sp e ci f ic m ole c u lar c la ss es Figure 1 | T rends in cLogP and molecular mass in launched drugs. The rela tion ships betwe en media n cLogP ( a ) or mol ecul ar mass ( b ) and launch or publi cation date s fo r 592 or al d rug s appr oved wor ldw ide bet wee n 1983 and 200 7 are shown. The publication data exclude 29 drugs published pre-1964 or post-2001. Launch and publication dates differ by a media n of 1 0.5 yea rs, con sist ent wit h drug devel opme nt time f rames . For eac h launch yea r , 10\u2013 100% of the drugs occ upie d a m edi an publi cat ion time of 20.6 years . Hence, usi ng publi cat ion dat es 6 gives a better vie w of c ont emp or ary pr act ice tha n launch dat es. The res ult s of str aight line fits ar e: m ole cul ar mass publi cat ion : r 2 = 0.70, slope = 5.2, p 1; molec ula r mass launch : r 2 = 0.27, slope = 2.1, p = 0.00 76; cLog P public ati on: r 2 = 0.17, slope = 0.034, p = 0. 010 ; cLo gP launc h: r 2 = 0.095, slo pe = 0 .02 2, p = 0.1 3. The size of t he squar es repr esents the mea n Lip ins ki scor e wi th ran ge 0 (sm alle st) to 1 ( large st) (s ee al so Su pp le me nt ary in form at io n S5 (box ) p an el s 1,2 ). Figure 2 | T rends in drug appr ovals and their molecular mass. The number of or al drugs approved per annum worldwide from 1983 to 2006 and the percentage of these drugs that have molecular mass are shown. ANAL YSIS NATU R E R EV IE WS | DRUG DISCO VER Y V O L U M E 6 | N O V E M B E R 2 0 0 7 | 883 © 2007 N a ture Publi s hi n g G r o u p Natur e Review s | Drug Disco very Pr omiscuity (no. >30% inhibition at 10 µ M) 50 60 70 40 30 20 10 0 2.5 2 3 3.5 4 1 2 3 4 5 6 7 a Colour b y median rings: Median cLogP Pr omiscuity (no. >30% inhibition at 10 µ M) 50 60 70 40 30 20 10 0 280 300 320 340 360 380 420 400 b Median molecular mass (Da ) cLogP median pr omiscuity 20 40 60 10 8 6 4 1 2 Base Acid Neutr al Quaternary base Zwitterion \u20132 1\u20132 \u20132\u20130 0\u20131 2\u20133 3\u20134 4\u20135 5\u20136 > 6 c Colour b y ionization: cLogP Molecular mass (Da) median pr omiscuity 20 10 1 2 4 6 8 2 2\u20132.5 2.5\u20133 3\u20133.5 3.5\u20134 4\u20134.5 4.5\u20135 5\u20137 > 7 d Molecular mass ( × 100 Da) 83 144 4 164 158 7 12 16 27 21 19 16 32 5 85 14 57 104 9 191 6 166 53 42 37 116 28 18 99 28 60 7 6 50 195 73 66 173 21 13 99 78 49 52 6 12 10 39 3 3 136 81 9 41 17 28 36 16 38 22 17 6 14 211 56 7 85 81 9 13 20 6 34 30 40 12 62 46 14 32 9 Phar maco phor e The ensemb le of st eric and elec tro nic featur es t hat is nece ssar y to ensu re optima l inte rac tion s with a spe cific biol ogic al targ et structu re and to trigger (or to bloc k) its biolog ical resp onse . with c ommon substr uctures or pharmacophores 17 . For exa mpl e, u sin g p ub lic a tio n da tes from P rou df oot 6 , ther e ar e tim e-r ela ted inc rea ses in mo lecul a r mas s wi th yea r of pu bli ca tio n i n be nzodi az ep ines , \u03b2 -a dr enoc ep tor an tago - ni sts , hi sta min e H 2 an ta g o nis ts, di hy dr o pyr idi ne ca lci um - ch ann el bl ock er s, no n-s te ro id al an ti-i nfla mm at o ry dru gs a n d qu in ol on e an ti b io ti cs ( S up pl em en ta ry inf or ma tio n S2 (bo x)) . The re duct ion in the prop ort ion of l aunched low- mol ec ul ar-mas s or al dr ug s ov er ti me cor rel ates wit h the established decl ine in new dr ug l aunches 21 (FIG. 2) . Al tho ugh we do no t pr opo se th at th is pr ovi des a co m ple te ex pla na ti o n o f th e dr op in p r od uct ivi ty expe rie nce d b y th e pha rmaceu tical indu stry , a s th ere ar e several other poss- ible r e aso ns 21 , the possib ility that i t has been an im por - tan t co n tribu tory fa ctor deserves serious considera tion. Figure 3 | Promiscuity analysis. T op: rela tio nsh ips betw een m edian cLogP ( a ) or mol ecu lar mass ( b ) and prom isc uit y of 2, 133 dr ugs and r ef er ence co mpou nd s in 200 ass ay s fr om th e Cer ep BioP rint da ta ba se . Pro misc ui ty is the num ber of hi ts for each com pou nd, in which >30 % inhibi tio n was fou nd at a concen tr ation of 10 µ M . P oints ar e co lou re d by m edi an ring cou nt an d siz ed by eith er me di an mo le cu lar ma ss (281 .3 \u201358 2.9 Da) ( a ); or me dian cL og P ( 0.6 3\u20137 .15 ) ( b ) ; pr om is cui ty poi nts wi th co mp oun ds a re om itt ed . T he r es ul ts of str ai gh t line fi ts ( n = 64) ar e c LogP : slop e 1 6.1, r = 0. 83 , p = 1. 4 × 10 \u2013 17 ; mo lec ular mass : slop e = 0. 27, r = 0.46 , p = 0.0 01 3. Th e cLo gP re lati on sh ip ap pe ar s sigm oida l and ca n be fitt ed to a l og is ti c ex pr essi on ( r = 0.8 4) . Bot tom : t he ef fe ct of io ni za ti on st at e, r el at io ns hip be twee n med ian lo g p rom is cu ity an d b inne d cL ogP ( c ) and mo le cu la r mass ( d ) . L abel s ar e the num ber of comp ound s per po in t; po in ts wi th co mp ou nd s ar e omit ted. Th e tota l n umbe rs of co mp ou nd s ( n ) in eac h ion iz at ion cl ass and me di an (m ea n) pr omi scu ity val ue s ar e: aci ds n = 28 4, 3 (5 .1) ; b ases n = 813, 23 (25. 2) ; neut ral s n = 867 , 5 (8 .4 ), zwi tter io ns n = 99 , 3 (4 .7 ) and qu at er nar y b ases n = 70 , 10 (19 .1) . T he follow ing equation descr ibes promisc uity trends for th e whole data s et: Log Pr omiscuity = 0.075 cL ogP \u2013 0.71 A \u2013 0.54 N \u2013 0.4 7 Z + 1.0 0 ( n = 21 33 ; r = 0.65 ; s = 0.4 2; p for al l var ia bl es and in ter ce pt 10 \u2013 25 ; A, N and Z ar e i ndic at or var iabl es , set eq ual to 1 for acid s, ne ut r al s and zw it te rio ns res pe ct iv el y). Se e als o Su ppl emen ta ry in fo rm at io n S5 (box ) p an el s 3\u20136 . ANAL YSIS 884 | N O V E M B E R 2 0 0 7 | V O L U M E 6 w w w. n a t u r e . c o m / r e v i e w s /d r u g d i s c © 2007 N a ture Publi s hi n g G r o u p Natur e Review s | Drug Disco very Median cLogP 4.6 Astr aZeneca GlaxoSmithKline Mer ck Pfizer 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 a Pr ous GVK Pr ous GVK 2001 2001 2001 2001 2002 2002 2002 2002 2003 2003 2003 2003 2003 2003 2003 200 3 2004 2004 2004 2004 2004 2004 2004 2004 2005 2005 2005 2005 2005 2005 2005 2006 2006 2006 2006 2006 2006 2006 2006 Median molecular mass (Da ) 480 Astr aZeneca GlaxoSmithKline Mer ck Pfizer 390 400 410 420 4 30 440 450 460 47 0 b 2001 2002 2003 2003 2004 2004 2005 2005 2006 2006 2001 2002 2003 2003 2004 2004 2005 2005 2006 2006 2001 2002 2003 2004 2003 2004 2005 2005 2006 2006 2001 2002 2003 2003 2004 2004 2005 2005 2006 2006 2005 The re is ampl e ev id enc e th at m ore ex tre me phys ic al pr op e r t i e s an d t h e re fo re m o re c o mpl e x m ol e c u l e s wi ll have c oncom itant ly in cre as ed pre dic te d r isk s to de ve lo pa bi lit y \u2014 in clu d ing bi o ava il ab il it y , p e r me a- bility , solubility , synthe sis and formulati on \u2014 thereby decr easin g chances of succes s thr ough the develop ment pr ocess 4 ,22 . Pr omi scui ty The f act t hat dr ug lip oph il icit y is cha ngi ng l ess ove r tim e than ot her physic al proper ti es sug gests t hat this is an esp ecially importan t dr ug-like pro pert y , the con - trol of which is important for ultimate success in drug devel op men t. This is n ot surprisin g: th e r ole of LogP i n infl uen cin g drug po te ncy , ph arma co kine tic s an d tox ic i ty has been establish ed for man y years 22\u201326 . This pro p erty essentially reflects the key event of molecular desolva- tion in tr an sfer fr om a queo us ph ases to c ell membra nes and to protein bind ing sites, whi ch are most ly hydro - phob ic in na ture. I f lipop hilicity is too high, there is an increased likelihood of binding to mul t ip le targets and res ulta n t p harmacol ogically ba sed t ox icol ogy , a s well as poor solu bility an d m etabol ic clea ranc e. The Cer ep Bio Prin t database of drugs and r eferen ce com p ou nds pr ovides a unique op p ort unity to exa mine t he ro l e o f p hy si c a l p rop e r t i es i n i n f lu e nc i ng d r u g promiscuity and s ide e ffects 27,28 . I t is clear that overal l pr omisc ui ty is pr edomi nan tly con trol led b y lipo phili ci ty and io nizatio n state (FIG. 3) . Bases a nd qua ternary bases ar e no t ab l y m or e p ro m is c u o us t h an a c i ds , n e ut r a l compoun ds or zw itteri ons ( FIG. 3 an d Supplement ar y info rmatio n S 3 ( box) ), bu t in all i oniz ati on classes, pro- miscui ty c orr elate s positiv ely with cLogP (or AC DLogP , AZLo gD7.4 a nd per cen tag e of P SA, wh ich ar e corr ela ted wit h c Lo gP ). Int ere st ing ly , t he nu mb er of r in gs a ls o show s a relat ions hip wit h prom is cu ity , alt hou gh th is tren d ca nnot be di stin guish ed fr om li p op hilicity . The ove ral l relat ionsh ip be twee n promis cu ity and m ol e c u l a r m a s s i s c o mp l e x (FIG. 3b ,d) . B a s e s s h ow op t im a l pr om i s cu it y i n t h e 3 50 \u2013 5 00 - D a r an ge a nd ne u tr a ls app e a r t o b e s im i l ar ; h ow e ve r , w it h a c id s , t he re is a p os it iv e c or re l at io n b e tw e en pr om is c ui ty and molec ular m ass (F IG. 3 d) . T he results in FI G. 3 were corrob orated by an alysi s of cross -sc reening d ata w ith As traZenec a pro ject co mpoun ds, whic h show ed s imila r over al l t ren ds wit h i oni zat ion , cL og P a nd m ole cu la r mass. Thes e resul ts co ntrast wi th a published analysis 29 of hig h-th roughput sc reeni ng d ata, us ing 220 dive rse target s an d 7 5,000 comp ounds, in wh ich promisc uity de cr ea se d pro por t io na ll y wit h i ncr ea si ng mo le c ul ar mas s; perha ps th e BioP rin t data set is too small to rev eal th is tr en d. In a dd it io n to bu l k l ipo ph il ic it y , s pe c if ic t hr e e -d i me n s io na l ph a r ma c op ho r i c a nd s tr u c t ur a l fe atu res i nc lu di ng hyd ro ge n b ond in g, p ol ar iz ab il it y and ster ic constr aints, whi ch are not fully represented by molecular mass, will driv e t he magnitude of binding affinity for pr ote in active sites. Pro miscuity is necessary for the action of s ome drugs, especially central nervous sys tem age nts, but it i s cle ar th at d elib er ate des ign of mu l t ip l e- a c t i ng c o mp o un d s at s e l e c te d t a rg e t s, a n att ra c ti ve t he rap e ut ic pr op os iti on , i s a c ons id er abl e Figure 4 | T rends in clogP and molecular mass in r ecently patented compounds from four pharmaceutical companies. The median values of c LogP ( a ) or molecular mass ( b ) labelled by year obtained fr om WO patent databases (see BOX 1 for explanation of WO patent). Pr ous Science Integrity data covers 2001\u20132006 (blue) and GVK Bio patent data 2003\u20132006 (r ed). P oints ar e sized by mean Lipinksi score (a value of 1 for each rule of 5 violation per compound; r ange her e is 0.30\u20130.74). Aggregating the data and comparing companies gives the following statistically significant differ ences (for Student\u2019 s t test, p values Supplementary information S 5 (box), panels 7\u201312): Prous Science Integrity cLogP: AstraZeneca versus GlaxoSmithKline versus Mer ck 0.0018; Astr aZeneca versus Pfizer Merck 0.034; GlaxoSmithKline versus Pfizer Merck versus Pfizer GVK Bio cLogP: AstraZeneca versus GlaxoSmithKline 0.0004; GlaxoSmithKline versus Mer ck 0.036; GlaxoSmithKline versus Pfizer versus Pfizer Science Integrity and GVK Bio molecular mass: Pfizer versus the other companies ANAL YSIS NATU R E R EV IE WS | DRUG DISCO VER Y V O L U M E 6 | N O V E M B E R 2 0 0 7 | 885 © 2007 N a ture Publi s hi n g G r o u p Natur e Review s | Drug Disco very Median molecular mass (Da ) Median cLogP 400 420 480 460 440 380 360 340 320 300 2.5 3 3.5 4 4.5 Or al drugs Astr aZeneca (AZ) GlaxoSmithKline (GSK) Mer ck Pfizer All GVK compounds Development c ompounds Pr e-1983 ( n = 1,526) 1983\u20132007 ( n = 5 92) Mer ck GVK ( n = 519) AZ GVK ( n = 440) Phase I and I\u2013II ( n = 91) Phase II and II\u2013III ( n = 214) Phase III and pr e-r eg ( n = 126) Pfizer Prous ( n = 918) Pfizer GVK ( n = 447) AZ Pr ous ( n = 855) Published post-1990 ( n = 106) ( n = 117148) GSK Pr ous ( n = 921) GSK GVK ( n = 497) Mer ck Pr ous ( n = 822) phy si c oc he m ic a l c ha l le ng e 3 0 . A lt ho ug h pro mi s cu it y will be less impo rtant if selectivity for the desired target is h igh, the lesson from t his analysis is t hat the risk of unwa nted phar mac olo g y in cre as es w ith lip oph ili cit y and is dep enden t on ioniza t ion class 66 . Cu rr ent m edic in al che mi st ry The four c ompani es w ith t he m ost pro lif ic c ontr ibu - tion to the rece nt small-molecule drug disco very paten t liter at ure hav e dif ferin g year-b y-year ph ysical-pr operty pro f iles amon g their paten ted compo unds (FIG. 4) . This mi ght b e e xp ec te d g ive n t he ti me sc al es of di sc over y ch e m is t r y a n d p ro j e c t p a te nt d e li v er y , a n d o ve r a l l proj e ct p or t fol io s in a g iv en ye ar. How ev er , lo o ki ng at t h e pr op er t y d is t ri but i ons ove r t h e w ho le p er io d examined (2001\u20132007 f or Pro us Science In tegrity data, 20 03 \u2013 20 07 f or G V K Bi o d at a) , t he re a re s ig n if i can t differences between the companies. The rank or der of cL og P an d mo lec u lar mas s va lue s a gre e for bo th the Prous Sc ience In te grity and GV K Bio patent data. For med ian cLogP , Gl axoS mith Kli ne > M erc k > As traZen eca > Pfizer; for median mo lecular mas s, GlaxoSmithKline = Merc k = As tr aZ ene ca > Pf iz er . The over al l c orre s- ponde nce between the two databa ses pro vides corrobo- ration for the observed trends. The o n ly differences are the Ast raZ enec a cLo gP compari sons wit h Merck and Pf i ze r , w h i ch are s ta ti st i ca l ly d if f er ent i n t h e P rou s Scie nce Integrity d ata (with more data p oints) but not in the GVK Bio pa ten t da ta. T ak in g t he ave ra ge prop e rt y va lu es for G VK Bi o co mpo un ds a ggr ega ted fr o m al l co mp ani es c onf ir m s th at the mov em en t o f ch emical spa ce in curr ent ch emi stry to higher molecular mas s and cLogP has pr ogressed even furth er fro m hi st or ical o ral dru gs, r ecent oral dru gs an d deve lopm en t com pou nds . Th ese co mpari sons a re sum- marized in FIG. 5 . The median pat ent ed compoun d has a cLogP of 4.1 and molecular mass of 450 Da, whereas the most rece n t ora l drugs , disco ver ed since 1990, hav e a me di a n cL og P of 3.1 and mo lecu la r mas s of 43 2 Da . Ev en in th e 200 1\u2013 200 6 peri od, th e up war d tr end in bo th cL og P a nd mo lec ul a r mas s is co nt in ui n g in th e agg r ega ted P r ous Science In te gri ty data . On e re as on wh y p hy si cal pr op er ti es ma y be i ncr ea si ng is th a t ma ny o f toda y\u2019 s drug p ro tein ta rget s a re diff er ent fro m those ex plo red hist ori cally . I t is clear th at the fo ur co mpa nies in thi s stu dy ar e pur suin g kina ses an d GP CRs resp onding to pept idi c li gands as sig nif icant c ompo - nen ts of the ir portf ol ios ( S up plem en tary i nf or ma tion S4 (ta ble) ). Am ong drugs l a un ch ed si nc e 198 3, th ese clas ses a r e a min ori ty , wi th onl y 7 ki nas e in hib it or s an d 14 GP CR pep tid e inhib ito rs. Com pariso ns of targ et-cl as s pr ope rty pro f iles of cur ren t pat ents with oral drugs ar e summa- rized in FIG. 6 , using the aggrega ted data from the four co m pan ies a nd the GP CR p ep tide and kin ase da ta fro m the i ndi vid ual co mpa nie s. T wo ma in tre nd s emer ge fr o m FIG. 6 : fi rst, the ph ysical pro perti es of most established drug cl as ses ar e being inflat ed in curr en t c hemis tr y; se c- o nd , the co mpa n y di ffer en ce s seen in al l pa te n ts per sis t in mos t ca ses amo ng the kin ase an d GPCR pepti de tar get s. Th e ma jor co mpo un d tar get cl ass in o ral drugs a pp r o ve d sinc e 1983 i s the am iner gic GPCR rec ept or (20% o f the drugs), which is gen erally con sidered highly druggable as th e endoge nous lig ands (s erotonin, nor adrena line, his tami ne a nd ac etylc ho line ) ar e small mo lecules . Ev en in this receptor class, both molecular mass and cLog P ha ve s ignifica ntl y in cr ease d in curre n t ch emi stry . Th e f in a l co mp ar i so n b et w ee n t he c omp an i es i s perha ps the m ost inte res ting. Chemokine GPCR recep - tors, responding to pepti de li gands, have b een among the more dif fic ult target cl asses in te rms of c ontrol of ph ysical pr operti es of an tagon ist s. The che mok ine (C-C motif ) receptor 5 (CCR5) has been an a rea of co nsider- ab le i nt er es t fo r t re at m ent o f H IV a nd r he u mat oi d arthr itis, with the Pfiz er CCR5 antago nist maraviroc 31 bein g the mos t adva nced, ha vin g rece n tly b een ap pr ov ed fo r the tr eatmen t of HIV . The four compan ies arrived at the same chemica l cl ass of CCR 5 antagonist, contain - ing a common phen ylpr op ylpiperidi ne pharma cop hor e (FIG. 7) , a s maj or c omp one nts of t he ir e f for ts on t h is tar get 31 \u201334 . I n this c om poun d cla ss ther e is a sp read of 2.3 units in cLogP and 110 Da in molecu lar mass between com panies (FIG. 7) . The physical properties o f the C CR5 ph eny lp ropy lp ip er i di ne c omp ou nd s ar e s t ati st i ca l ly diffe r en t b y com pan y and thi s sin gle clas s of com poun ds mirrors the ov erall compan y trends seen in FIG. 4 . This single target analysis strongly suggests that differences in physica l propert y inf lation be tween compan ies are due to differences in local medicinal chemistry practice an d t h e em ph as is ( or no t) pl a ce d on t he c ont ro l o f ph ysical pr operties. Figure 5 | Overall trends in median cLogP and molecular mass in compounds from four pharmaceutical companies. The fi gur e com pa r es hi st or ica l o ral drug s, co mpo unds in de ve lo pm en t and in cur r en t pat en ts fr om Astr aZe ne ca , Glax oSmi th Kli ne, Me r ck and Pf izer . P oi nts ar e colo ur ed and lab el le d by sour ce, and siz ed by mea n L ip ink si score (a value of 1 for each rule of 5 violation per compound; r ange here is 0.26\u20130.74). n = numb er of comp ou nds , o r n umbe r of pate nts for GV K Bio . Fo r t he aggr egat ed Pro us Sc ien ce Inte gr it y data ov er th e per io d 2001 \u2013200 6, th er e ar e up wa r d pro pert y tr en ds : the r es ult s o f s tra ig ht li ne fi ts of pr oper ty vers us ye ar are mo le cu la r mass , s lope 2. 0 Da (bo th mea n, r = 0.61 and med ian , r = 0.62, not signif ica nt) and cLo gP slope 0.0 6 (mean, r = 0.81, p = 0 .05) an d 0.0 2 (med ian, r = 0. 31 , not si gn if ic ant ). ANAL YSIS 886 | N O V E M B E R 2 0 0 7 | V O L U M E 6 w w w. n a t u r e . c o m / r e v i e w s /d r u g d i s c © 2007 N a ture Publi s hi n g G r o u p Natur e Review s | Drug Disco very Median cLogP 4.5 5.0 5.5 4.0 3.5 3.0 2.5 2.0 GPCR lipid Nuclear hormone r eceptor GPCR amine T ransporter Ion channel Pr otease GPCR peptide Kinase Astr aZeneca All four Or al drugs 1983\u20132007 GSK Mer ck Pfizer a Median molecular mass (Da ) 500 525 550 47 5 450 425 400 37 5 350 325 300 Astr aZeneca All four Or al drugs 1983\u20132007 GSK Mer ck Pfizer b Colour b y tar get: GVK patents Or al drugs 1983\u20132007 Pr ous GVK compounds Shape by sour ce data: P er sp ec ti ves Des p it e the ap par ent wides pr ead acce pt an ce of dru g- lik e principles over t he p ast d ecade, the trends in physical propert y inf lation s een wit h recent ora l drug s is con - tin uing i n curr ent m edic inal ch emi stry (FIG. 5) . W hy a re chemi sts st ill synth esiz ing large r and more lip ophil ic co m pou nd s? W ith abso rpti on, distr ib ut io n, meta bolism and excre tion (ADM E) opt imi zation now a st anda rd com ponen t of drug disco very pro gram mes 22 , per sis ten t effort may pay off and result in compounds with good o ra l bio av a il a b il ity th at ha ve ph ys ical p r ope rt ie s in \u2018 exc ep- tio n chem ical spa ce \u2019 ver su s o ral drug s. Rec en t exam ples of h igh -mol ecula r -mas s oral drug s in cl ude HI V p ro tea se inhi bit ors an d an gio tens in II r ecep tor a n tag onis ts; a ddi - tionally , in a GlaxoSmithKline st udy , rat bioa vailab ility was claimed to be unrela ted to molecular mass 9 . Thus, pharmacokinetically acce ptab le chemical space c an be foun d b ey ond th e r ul e- of-f ive gu ide lin es. Inc reas ing li pop hil ici ty will a lso te nd t o inc r ease b in din g af fi ni ty 23\u2013 26 , so the pur suit o f lipo ph ili c, lar ge , po te n t an d bi oa vaila ble co mpo und s in cur ren t med icin al ch emis try pr ogra mme s pro bably explains the observed pro perty infl a tion. H ow ever , th e most importan t c hallen ge to the med i- cinal chemist to day is not just obtaini ng high potenc y and good ADME, but also deliver ing candidate drug s that will not event ually fail owing to other com p ound- re lat ed pr o pert ies , es peciall y tox ici ty . The im pl ica tio ns of workin g increasingly closer to the extremities of drug- like chemical space a ppear serious fo r ov erall prod uct- ivity (FI G. 2) and pro miscuity leading to increas ed risks of pharm acolo gica lly b ased toxicity (FIG. 3) . Althoug h mor e difficult targ et druggabili ty 19,20 is pla ying a role in ph ys ic al -p ro perty ex pa nsi o n, the ef fe ct of loc al med ici na l che mic al dec isi on-m aki ng i s si gni fi cant as s hown by the differ ences between co mpa nies (FIG. 4) . In addi t io n, changes in me dicin al chemist r y pract ice appear to b e driving physical-propert y inf lation in both newer and some ol der tar get classes (FIGS 6,7) . W e su gg es t tha t c o m po un d li pop hil ici ty , a s es ti ma ted b y c Log P , is the m ost im porta nt mo lecul a r p ro pert y 23\u20132 6 , Figure 6 | T arget class trends in cLogP and molecular mass. The median values of cLogP ( a ) and molecular mass ( b ) by drug tar get class, comparing oral drugs launched fr om 1983\u20132007 with individual companies (AstraZeneca, GlaxoS mithKli ne (GSK) , Mer ck and Pfizer\u2019 s G-pr otein-couple d (GPCR) p eptide and k inase target s) and the agg reg ated compan y data (all ta rge ts). P oints colou red b y tar get class, s ized by med ian molecular mass (3 07 .8\u2013531.0 Da) ( a ); or cLo gP (2.44 \u20135. 41) ( b ); and shap ed by sou rc e data. C ompari son o f co mpa nies was by Studen t\u2019 s t tes ts ( p val ues , ND = not dif fer ent ( p >0.05 )), see S upplem ent ary info rma tion S5 (box) , panel s 13\u201324) . For GPCR peptid es, cLog P stati stic al valu es (Pr ous Science Integr ity, GVK Bi o patents ) are : GlaxoS mithKli ne versu s Pfizer , 0.012, 0.0001 ; GlaxoSm ithKli ne versus Astr aZene ca, 0.0032, 1; GlaxoS mithKl ine vs Mer ck, ND, 0.025; Merck versus Pfizer 0.027, ND; Mer ck vers us Astr aZene ca 0.011, N D; Astr aZeneca versus P fizer , ND, ND. F or mol ecular m ass, statistical v alues (Prous Science Integr ity, GVK Bio p atents ) are : GlaxoSm ithKli ne versus P fizer , 0.030, 0 .0084; G laxoSmi thKlin e versus As tr aZeneca , ND, ND; GlaxoSmithKl ine versus Mer ck, 0.000 6; Mer ck versus Pfizer , 01, Mer ck versus Astr aZenec a, 0.0002 , 0.0078; A str aZenec a versus P fizer , 0 .0019, 0.0007 . F or kina ses, cLogP s tatist ical values (Pr ous Science Integr ity, GVK Bio patents) are: GlaxoSmithKline versus Pfizer , 0.0097; GlaxoSmithKline versus AstraZeneca, ND, ND; GlaxoSmithKline versus Merck, ND, ND; Mer ck versus Pfizer , ND; Mer ck versus Astr aZeneca, ND, ND; AstraZeneca versus Pfizer , 0.0068. For molecular mass, statistical values (Prous Science Integrity, GVK Bio patents) ar e: GlaxoSmithKline versus Pfizer , ND, ND; GlaxoSmithKline versus Astr aZeneca, 0.0005, GlaxoSmithKline versus Merck, ND, ND; Mer ck versus Pfizer , ND, ND; Mer ck versus Astr aZeneca, 0.0002, 0.0002; AstraZeneca versus Pfizer , ANAL YSIS NATU R E R EV IE WS | DRUG DISCO VER Y V O L U M E 6 | N O V E M B E R 2 0 0 7 | 887 © 2007 N a ture Publi s hi n g G r o u p N 1 Natur e Review s | Drug Disco very CCR5 cLogP 5 6 4 3 2 1 0 Astr aZeneca GSK Pfizer Mer ck O NH F F N N N N N N O OH F N N F S O O N F F N O S O O N N O S NH 2 O O N N Pfizer (mara viroc) Molecular mass 514 Da; cLogP 3.3 Mer ck Molecular mass 5 23 Da; cLogP 4.2 Astr aZeneca Molecular mass 6 33 Da; cLogP 2.3 GlaxoSmithKline Molecular mass 612 Da; cLogP 3.8 a CCR5 molecular mass (D a) 575 600 550 525 500 47 5 450 425 400 Astr aZeneca GSK Pfizer Mer ck b Mean Median Mean Median Phos phol ipid osis Phosphol ipidosis is a lipid stor age disor der in which e x cess phospholipids accumula te within cells. Dru g-i ndu ced phosph olipid osis occur s with many c ationic amphiphi lic drugs . as it is changing less over time in launched oral dr ugs tha n ot he r pr oper tie s (FIG. 1) . Li pop hili ci ty pl ays a d omi- na nt rol e in pr o mo tin g bi nd ing to un wan ted drug ta r ge ts (FIG . 3) . L i po ph ilic ba ses c an cau se ca rdi ova scula r to xic o- log ical eff ects b y b indin g to th e HE RG (h uman eth er -a- go -g o- re lat ed pota ssi um c han ne l p rot ein; also kno wn a s K CNH2 ) i on cha nn el 35 an d tiss ue to xici ty b y pr o mo ting ce ll ula r ph os ph ol ip id o si s 36 . Bu t me dia n cu rr en t co m po un ds from me dicina l chem istr y progr ammes c onducted in leading pharma ceutical companies have cLog P values th a t h a v e in cre as ed by ~1 .5 lo g un its re lat ive t o or al drug s la unc he d fr om 19 83 \u201320 07, a nd b y ~1 lo g u ni t re lat iv e to th e mo st r ece n tl y disc o ve red ora l drugs . In ad diti on, 30% of the pa te n ted co m pou nd s fr o m the fo ur co m pan ies in thi s stu dy ha ve cL og P va lu es >5 (t he ru le-o f-fi ve cu t-o ff ). All thes e data sugge st th at the high ly lip ophilic com- po und s bei n g mad e in ma n y drug di sco ve ry p r og ram mes tod ay car ry in cr ease d risk s o f d evel op me n tal at tri tio n. Ligan d efficie ncy (LE) is a n importa n t new c on cept , which estimates the e fficiency of a binding interaction with respect to t he magnitude of ligan d physical pro p- er t ies , mo st n ota bly s iz e (e qu ati on 1) 37 . W e prop o se maximizing the minimally acceptab le lipophilicity per uni t of in vi tr o poten cy , or ligan d-lipo philic it y efficie ncy (LLE, equation 2) 37 , as a more import ant object ive for lead gen era tion a nd op timizatio n pr ogram mes. LE = pI C 50 (or p K i ) ÷ n umber o f heavy ato ms (1) LLE = p IC 50 (or p K i ) \u2013 cLog P ( or L ogD) (2) Figure 7 | CCR5 as an example. Representative structures and physical pr operties of published chemokine (C-C) receptor 5 (CCR5) antagonists based on a common phenylpr opylpiperidine pharmacophor e 1 fr om Pfizer 31 , AstraZeneca 32 , Merck 33 , and GlaxoSmithKline (GSK) 34 . The mean and median values of cLogP ( a ) and molecular mass ( b ) abstr acted fr om the GVK Bio database for all the companies patented CCR5 receptor antagonists containing pharmacophore 1. The numbers of phenylpr opylpiperidine compounds and the pr oportion this r epresents of the companies\u2019 total CCR5 patented compounds are: AstraZeneca 1,069, 87%; GlaxoSmithKline 690, 46%; Mer ck 2,467, 82%; and Pfizer 309, 78%. Error bars are standard errors of the mean. Comparing companies gives the following statistically significant paired differences (Student\u2019 s t test, p values see Supplementary information S5 (box), panels 25,26): cLogP: all comparisons p except GlaxoSmithKline versus Merck, not significant. Molecular mass: all comparisons, p ANAL YSIS 888 | N O V E M B E R 2 0 0 7 | V O L U M E 6 w w w. n a t u r e . c o m / r e v i e w s /d r u g d i s c © 2007 N a ture Publi s hi n g G r o u p The a verage o ral drug wi th cLogP ~2.5 and po tency in the range ~1\u201310 nM suggests an LLE t ar get of ~5\u20137 or greater . High in vivo potency has advan tages: when the tot al dose in hu ma ns is lo w , adve nti tio us com poun d- re lat ed to xici ty is le ss of an is sue 38 . I n es sen ce, the go al f o r optimiza t ion is to increase p oten cy witho ut increasing li pop hilici ty a t th e sam e tim e. Th e di ff ere nc es b et we en c ompa nie s i n th is s tud y are in t riguing, and ar e impo rtant because the paten ted com pound ph ysicochemical p ro files, and an y poten tial res ultin g develo pm en t risk s, a re like ly t o be r ef lected in the c om pa nies \u2019 p i pel ines . I t is perha ps n ot s urpr is in g tha t the com pan y wit h the lo west com pound mol ecula r mas s an d cLog P is Pfi zer , in whic h the rule of five orig ina ted 1,2 and where pro perty- based design has been practised for some tim e 22,39,4 0 . Ident if ic ation of th e l ea d c ompou nd, or che mi cal sta rting po in t, fo r a drug dis co very pr ogra mme ha s been hig hli ghted re centl y as a cr itic al ly impor tant ac tiv ity , re f le ct e d by l ea d ge ne rat i on st r ate gi es b ei ng w id ely impl eme nted i n t he ph arm ace uti ca l ind ust r y 41\u201346 . In part icula r , th e co nc ep ts of l ead-lik eness 47 an d frag men t- lik enes s 37,48 tha t follo wed drug-l ike nes s pr opo se tha t i t is ad va nta geo us to us e sm all , hy dro phil ic mol ecule s to sta rt dr ug d isc over y proj ec ts. Thi s al lows the proc ess es of chem ical opt imi za tion, which frequ entl y incr ease ph ysi- cal pr operties 13, 17,47,49 ,50 , to wo rk wi thin drug -lik e spac e. Perh aps t he se st rate gi c d ev elop ment s, w hi ch c le arly em ph as ise \u2018 sma ll is bea u ti ful , \u2019 ha ve ye t to be full y acc ept ed or implemented? M edicinal chemists will additionally be i nflu enced by othe r f act or s in th eir de cis io n-makin g: their and their colleague \u2019 s kno wledge and experience 51 , their intu itio n an d c rea tivity 52 , th eir use of r elevan t pr e- dictive too ls 39,40 , their ab i li ty to handle vastly incr e ased da ta flo w 53 an d ev en the ir pr eju dice 54 . Pu rs uit o f diff ere nt molecular targ ets does not seem to pr ovide an ob vious explanation for the differences b etween c om panies, as th e over al l t rends are s imi lar in cu rrent major targ et classes and in a single compound class (FIGS 6,7) . Local cu ltures, poli cies (or la ck of t hem), d isea se str ategies, approach es to o btain ing inte lle ctua l prop ert y , as we ll as speci fic project objec tives and the drive for shor ter drug discove ry tim elin es, will al so influe nce com poun d selectio n a nd op timizatio n tactics. Co nc lu si on Phy si co ch em ic al prop e rt ie s i n s ma l l-m ol ec u le d r ug disco very a re comp letely unde r the con tro l of medicin al che mists and can easily be ca lculated before chemical synthesis. W ith judicio us select ion of lead com pounds a n d co n s ta nt mo ni t o rin g of ph ys ic al pr op er ti es (es pec ial l y li pophilicity) during optimization, medicinal chemists ha ve an opport uni ty to hel p alleviate the appalli ng at tri- tio n ra tes , esti ma ted a t 93\u2013 96% (REF . 55) , i n c lin ica l drug de ve lopm ent . 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A ckno wledgeme nts W e gratefully acknow ledge nume rous fruitful discussions on physical properties with Astr aZeneca colleagues S. Boy er , D. C hes hi re , A. Da vis , J . Di xo n, D. L ath bu ry , J. Li , J.- E. Ny str öm , G. P air aude au , M. Rol f (wh o pr ovi de d Bio Pri nt dat a) , J. Ste ele , S. T eague and M. W enlock (who hel ped to assemble t he o ral dru gs dat abas e). J. Prou dfoo t (Boe hr ing er Ing el hei m Pha rma- ceu tica ls) v er y kind ly pr ovi ded hi s o r al dru g dat abas e . SUPPLEMENT AR Y INFORMA TION See online article: S1 (table) | S2 (box) | S3 (box ) | S4 (t able) | S 5 (bo x) ALL LINKS ARE A CTIVE IN T HE ONLINE PDF ANAL YSIS 890 | N O V E M B E R 2 0 0 7 | V O L U M E 6 w w w. n a t u r e . c o m / r e v i e w s /d r u g d i s c © 2007 N a ture Publi s hi n g G r o u p

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